The long term objective is to understand why and how certain environmental chemicals affect the liver. However, the immediate objectives are to study agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the chlorinated aliphatic hydrocarbons for effects on the liver and pancreas. For TCDD a major objective will be to develop a blood clearance test with certain drugs for the early detection of liver dysfunction by TCDD in animals that can ultimately be applied to man. Studies will be initiated to determine the mechanism by which TCDD depresses bile flow, plasma disappearance and biliary excretion of certain foreign compounds. Spironolactone and pregnenolone-16 alpha-carbonitrile will be assessed for ability to alter hepatic excretory signs of TCDD toxicity. Liver plasma membrane Na ion, K ion ATPase activity will be assessed for possible depression by TCDD treatment. Effects of other chlorinated diibenzodioxins, dibenzofurans, azobenzenes and azoxybenzenes will be compared to TCDD. Chlorinated aliphatic hydrocarbons and chlorinated benzenes will be studied for ability to enhance pancreatic fluid flow in various species and the mechanism and toxicological significance of the effect determined. Effects of ethionine, dimethyl-nitrosamine, and 1,1,1-trichloroethane will be compared to pancreatic effects of chlorinated hydrocarbons. With the retrograde intrabiliary injection (RII) technique, biliary absorption of organic and inorganic forms of heavy metals will be compared. Also the effect of treatment with hepatic microsomal enzyme and metallothionein inducers, bile salts, and chelating agents on biliary absorption and re-excretion of retrogradely injected metals will be assessed. TCDD and other chlorinated aromatic hydrocarbons will be studied with the RII marker compounds. With this combination of approaches a more thorough understanding of how toxic agents of environmental interest affect the liver and other soft internal organs such as the pancreas should emerge.